Efficient one-step synthesis of 3-amino-6-arylpyridazines

Article abstract of DOI:10.1016/S0040-4039(01)00134-4

Starting from the commercially available 3-amino-6-chloropyridazine, 3-amino-6-arylpyridazines were prepared in good yields by means of a Suzuki cross-coupling reaction avoiding the somewhat lengthy four-step classic synthesis.

Full text of DOI:10.1016/S0040-4039(01)00134-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2115–2117
Efficient one-step synthesis of 3-amino-6-arylpyridazines
Se´bastien Guery, Isabelle Parrot, Yveline Rival* and Camille G. Wermuth
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Universite´ Louis Pasteur,
Faculte´ de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France
Received 11 December 2000; accepted 18 January 2001
Abstract—Starting from the commercially available 3-amino-6-chloropyridazine, 3-amino-6-arylpyridazines were prepared in good
yields by means of a Suzuki cross-coupling reaction avoiding the somewhat lengthy four-step classic synthesis. © 2001 Elsevier
Science Ltd. All rights reserved.
The pyridazine ring has demonstrated many synthetic1
and several biological uses.2 Despite the useful nature
of pyridazines, there are a limited number of synthetic
approaches to substitution on these electron deficient
rings, and functionalization of the pyridazine nucleus
continues to be of synthetic interest.3–5
Reagents other than ammonia were also examined.
Atkinson et al.10 have reported that the nucleophilic
displacement of the halogen by urea, followed by alka-
line hydrolysis leads to the expected compound with a
80% yield. Furthermore, Kappe et al.11 have substituted
the chlorine atom with sodium azide leading to a
tetrazolo[1,5-b]pyridazine, which was then transformed
into the corresponding amine via a Staudinger reaction.
The use of potassium thiocyanide in EtOH, followed by
hydrolysis of the intermediate thiourethane was also
described. But, the most current method is the substitu-
tion of the halogen by hydrazine followed by the
hydrogenolysis of the initially formed 3-hydrazinopyri-
dazine.12 The overall yields for this synthetic pathway
previously described were found in the 35–45% range.
The synthesis of 3-amino-6-arylpyridazines is possible
in four steps, but is somewhat lengthy.6–14
More particularly there is still a need for efficient
syntheses of 3-aminopyridazines. Effectively, among the
methods described in the literature for the preparation
of 3-amino-6-aryl pyridazines,6–14 ammonolysis of the
corresponding 6-aryl-3-halopyridazines6 proceeds with
extremely variable yields6–8 despite vigorous experimen-
tal conditions (autoclave, 100–200°C, copper catalysts).
Attempts to replace the halogen atom by other leaving
groups were also studied. Thus, 3-methylthio or 3-
ethylthio derivatives have been reacted with ammonia
to lead to the corresponding 3-aminopyridazines.8
Yanai et al. have reported the even more difficult
nucleophilic displacement of 3-alkoxyderivatives.9
Starting from 3-mesylated and 3-tosylated pyridazines,
Gregory et al. have demonstrated that the reaction with
ammonia gave compounds with similar yields to that
observed with 3-halopyridazines.8,14
In this paper, we describe a convenient approach to
3-amino-6-arylpyridazines from commercially available
3-amino-6-chloropyridazine by a Suzuki cross-coupling
reaction (Scheme 1) (Table 1).15 Such a reaction3,16 was
firstly applied to 3-chloro-6-methoxypyridazine and to
3-aminoalkyl-6-arylpyridazines.16 This one-step reac-
Pd(PPh3)4
Na2CO3 2M
NH2
Cl
NH2
B(OH)2
+
EtOH
R
R
N N
N N
1
2
3
Scheme 1.
Keywords: 3-amino-6-arylpyridazines; 3-amino-6-chloropyridazine; Suzuki cross-coupling; palladium(0) catalysis.
* Corresponding author. Tel.: +33 390 24 42 26; fax: +33 388 67 47 94; e-mail: rival@pharma.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00134-4

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S. Guery et al. / Tetrahedron Letters 42 (2001) 2115–2117
Table 1. Synthesis of 3-amino-6-arylpyridazines (3a–3k)
7. Wermuth, C. G.; Bourguignon, J. J.; Schlewer, G.; Gies,
J. P.; Schoenfelder, A.; Melikian, A. J. J. Med. Chem.
1987, 30, 239–249.
R1
NH2
N N
8. Gregory, H.; Overend, W. G.; Wiggins, L. F. J. Chem.
Soc. 1948, 2199–2201.
R2
R3
9. Yanai, M.; Kinoshita, T. Yakugaku Zasshi. 1962, 82, 857.
10. Atkinson, C. M.; Rodway, R. E. J. Chem. Soc. 1959, 6–9.
11. Kappe, T.; Pfaffenschlager, A.; Stadlbauer, W. Synthesis
1989, 666–671.
12. Sitamze, J. M.; Schmitt, M.; Wermuth, C. G. J. Org.
Chem. 1992, 57, 3257–3258.
Compounds
R1
H
R2
H
R3
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
¦
¦
¦
-OCH3
H
¦
-Cl
H
50
40
45
45
45
40
50
35
55
60
60
-O-CH2-O-
-OCH3
H
¦
-Cl
H
H
-OCH3
H
¦
-Cl
H
¦
-CH3
H
13. Murakani, H.; Castle, R. N. J. Heterocycl. Chem. 1967,
4, 555.
14. Morren, H. G.; Morren, H. G., Ed: Belgian Patent, 1951.
15. General procedure for cross-coupling reactions: A suspen-
sion of 3-amino-6-chloropyridazine (3.46 mmol, 1 equiv.)
(1), arylboronic acid (3.98, 1.15 equiv.) (2), sodium car-
bonate 2 M (3.7 mL, 7.34 mmol, 2.12 equiv.) in toluene
(20 mL) and EtOH (1.9 mL) was stirred under an atmo-
sphere of argon for 30 min. Pd(PPh3)4 (0.14 mmol, 0.045
equiv.) was then added and the mixture was heated at
110°C for 32 h. The toluene was removed in vacuo, the
residue diluted with H2O and extracted with EtOAc (3×5
mL). The organic layers were dried over sodium sulfate,
concentrated in vacuo and then purified by flash chro-
matography (AcOEt–MeOH 9:1, TEA 2%). Satisfactory
spectral data were obtained for all new compounds (3a–
3k): 3-Amino-6-phenylpyridazine (3a): white needles; mp
140°C; Rf 0.40 (AcOEt–MeOH 9:1) 1H NMR (CDCl3,
300 MHz) l 4.89 (m, 2H); 6.84 (d, J=9.5 Hz, 1H);
7.39–7.95 (m, 5H); 7.97 (d, J=9 Hz, 1H). 3-Amino-6-
(3,4-methylenedioxy phenyl) pyridazine (3b): yellow
needles; mp 166°C; Rf 0.55 (AcOEt–MeOH 9:1/TEA 2%)
1H NMR (CD3OD, 300 MHz) l 4.75 (m, 2H); 6.04 (s,
2H); 6.94 (d, J=8 Hz, 1H); 7.15 (d, J=9 Hz, 1H); 7.39
(d, J=6.5 Hz, 1H); 7.46 (s, 1H); 7.75 (d, J=9 Hz, 1H).
3 - Amino - 6 - (4 - methoxyphenyl)pyridazine (3c): white
needles; mp 195°C; Rf 0.16 (AcOEt–MeOH 9:1/TEA 2%)
1H NMR (CDCl3, 300 MHz) l 3.87 (s, 3H); 4.75 (m, 2H);
6.81 (d, J=9 Hz, 1H); 7.00 (d, J=6.5 Hz, 2H); 7.58 (d,
J=9 Hz, 1H); 7.91 (d, J=6.5 Hz, 2H). 3-Amino-6-(3-
methoxyphenyl)pyridazine (3d): white needles; mp 124°C;
¦
-CH3
H
¦
3j
3k
¦
-CH3
tion was used here for the first time with a pyridazine
bearing a primary amine, without any protection, in
order to obtain various substituted 3-amino-6-arylpyri-
dazines with yields ranging from 35 to 60%. We
observed that the use of phenylboronic acid bearing
methyl groups provided the best yields, probably due to
the electrodonor effect of the methyl substituent. Surp-
risingly, the same cross-coupling reaction with a methyl
or a methoxy group in the ortho position on the phenyl-
boronic acid does not require the replacement of
Na2CO3 by Ba(OH)2, a base conventionally used when
a sterically hindered boronic acid is involved in a
palladium cross coupling reaction.17 The use of another
type of catalyst (Pd2dba3/PtBu3)18 was also explored
but the yields were not higher than those obtained with
the conventional Pd(PPh3)4 catalyst.
In summary, starting from commercially available 3-
amino-6-chloropyridazine, we have demonstrated that
3-amino-6-phenylpyridazines can be efficiently prepared
in a one-step cross-coupling reaction. The advantages
of this alternative approach reside in increased yields,
easier operating conditions, mild conditions and a
clearly shorter synthetic sequence.
1
Rf 0.19 (AcOEt–MeOH 9:1/TEA 2%) H NMR (CDCl3,
200 MHz) l 3.83 (s, 3H); 4.51 (m, 2H); 6.83 (d, J=9 Hz,
1H); 7.24 (d, J=8 Hz, 1H); 7.37 (t, J=7.5 Hz, 1H); 7.64
(d, J=9 Hz, 1H); 7.72 (d, J=8.0 Hz, 1H); 7.83 (s, 1H).
3 - Amino - 6 - (2 - methoxyphenyl)pyridazine (3e): white
needles; mp 135°C; Rf 0.17 (AcOEt–MeOH 9:1/TEA 2%)
1H NMR (CDCl3, 300 MHz): 3.83 (s, 3H); 5.14 (m, 2H);
6.76 (d, J=9.0 Hz, 1H); 6.98 (d, J=8.5 Hz, 1H); 7.06 (t,
J=7.5 Hz, 1H); 7.37 (t, J=8 Hz, 1H); 7.71 (d, J=9 Hz,
1H); 7.81 (d, J=8 Hz, 1H). 3-Amino-6-(4-chlorophenyl)-
pyridazine (3f): white needles; mp 155°C; Rf 0.20
(AcOEt–MeOH 9:1/TEA 2%) 1H NMR (CDCl3, 200
MHz) l 4.87 (m, 2H); 6.84 (d, J=9.0 Hz, 1H); 7.44 (d,
J=7 Hz, 2H); 7.61 (d, J=10 Hz, 1H); 7.90 (d, J=7.0 Hz,
2H). 3-Amino-6-(3-chlorophenyl)pyridazine (3g): yellow
needles; mp 153°C; Rf 0.53 (AcOEt–MeOH 9:1/TEA 2%)
1H NMR (CDCl3, 300 MHz) l 4.87 (m, 2H); 6.84 (d,
J=9.0 Hz, 1H); 7.39–7.41 (m, 2H); 7.61 (d, J=9 Hz,
1H); 7.83–7.86 (m, 1H); 7.98 (s, 1H). 3-Amino-6-(2-
chlorophenyl)pyridazine (3h): white needles; mp 135°C;
References
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Katritzky, A. R., Ed.; Academic Press: San Diego, 1990;
Vol. 49, p. 1.
2. Heinisch, G.; Kopelent, H. In Progress in Medicinal
Chemistry; Ellis, G. P.; West, G. B., Eds.; Elsevier:
Amsterdam, 1992; Vol. 29, p. 141.
3. Turck, A.; Ple´, N.; Mojovic, L.; Que´guiner, G. Bull. Soc.
Chim. Fr. 1993, 130, 488–492.
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1994, 38, 1273.
5. Wermuth, C. G. J. Heterocycl. Chem. 1998, 35, 1091–
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6. Nakagone, T. In Pyridazines; Castle, R. N., Ed.; John
Wiley and Sons, 1973; Vol. 28.

S. Guery et al. / Tetrahedron Letters 42 (2001) 2115–2117
2117
Rf 0.10 (AcOEt–TEA 2%) 1H NMR (CDCl3, 300 MHz) l
5.21 (m, 2H); 6.80 (d, J=9.0 Hz, 1H); 7.36 (m, 2H); 7.46
(dd, J=6.5 Hz, J=2 Hz, 1H); 7.58 (d, J=9.0 Hz, 1H);
7.67 (dd, J=6.5 Hz, J=2 Hz, 1H). 3-Amino-6-(4-
methylphenyl)pyridazine (3i): white needles; mp 163°C;
7.24 (d, J=8 Hz, 1H); 7.37 (t, J=7.5 Hz, 1H); 7.64 (d,
J=9 Hz, 1H); 7.72 (d, J=8.0 Hz, 1H); 7.83 (s, 1H).
3 - Amino - 6 - (2 - methylphenyl)pyridazine (3k): white
needles; mp 126°C; Rf 0.50 (AcOEt–MeOH 9:1/TEA 2%)
1H NMR (CDCl3, 200 MHz) l 2.36 (s, 3H); 5.52 (m, 2H);
6.83 (d, J=9.0 Hz, 1H); 7.25–7.41 (m, 5H).
16. Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 7,
1163–1168.
17. Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992,
207–210.
18. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387–3388.
1
Rf 0.50 (AcOEt–MeOH 9:1/TEA 2%) H NMR (CDCl3,
200 MHz) l 2.41 (s, 3H); 4.80 (m, 2H); 6.82 (d, J=9.0
Hz, 1H); 7.29 (d, J=7.5 Hz, 2H); 7.62 (d, J=9 Hz, 1H);
7.86 (d, J=9 Hz, 2H). 3-Amino-6-(3-methylphenyl)-
pyridazine (3j): white needles; mp 132°C; Rf 0.54
(AcOEt–MeOH 9:1/TEA 2%) 1H NMR (CDCl3, 200
MHz) l 2.44 (s, 3H); 4.77 (m, 2H); 6.83 (d, J=9 Hz, 1H);
.